Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS
- 1Neurobiology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore
Abstract
MAPT (Tau) dysregulation is implicated in several neurodegenerative diseases, but its contribution to amyotrophic lateral sclerosis (ALS) is poorly understood. Here we show that mRNA isoforms encoding 4-repeat (4R) Tau are upregulated and cytoplasmically enriched in iPSC-derived motor neurons (MNs) from VCP-mutant and sporadic ALS, without a corresponding change in Tau protein. Using splice-switching antisense oligonucleotides and isoform-specific siRNAs, we find that enhanced 4R expression reduces MN viability, whereas its selective knockdown improves survival, with kinetics more consistent with an RNA-intrinsic effect than altered protein synthesis. Exon 10-containing MAPT RNA shows increased predicted secondary structure, self-association and altered Tau biocondensation in vitro. In post-mortem ALS cervical spinal cord, increased relative exon 10 usage is associated with a higher-risk clinical phenotype and shorter disease duration These findings identify an isoform-specific contribution of MAPT to MN vulnerability in ALS and nominate 4R MAPT RNA as a therapeutic target.
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BibTeX
@misc{crerar2026toxicity,
title = {{Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS}},
author = {H. Crerar and M. Stasi and K. Pal and S. Nuccio and M. Petric-Howe and G. Manferrari and Y. Wang and B. Clarke and M.-D. G. Ruepp and M. Di Antonio and R. Patani},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.22.753400},
url = {https://www.biorxiv.org/content/10.64898/2026.09.22.753400v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS
AU - H. Crerar
AU - M. Stasi
AU - K. Pal
AU - S. Nuccio
AU - M. Petric-Howe
AU - G. Manferrari
AU - Y. Wang
AU - B. Clarke
AU - M.-D. G. Ruepp
AU - M. Di Antonio
AU - R. Patani
PY - 2026
DA - 2026/09/22
PB - bioRxiv
DO - 10.64898/2026.09.22.753400
UR - https://www.biorxiv.org/content/10.64898/2026.09.22.753400v1
AB - MAPT (Tau) dysregulation is implicated in several neurodegenerative diseases, but its contribution to amyotrophic lateral sclerosis (ALS) is poorly understood. Here we show that mRNA isoforms encoding 4-repeat (4R) Tau are upregulated and cytoplasmically enriched in iPSC-derived motor neurons (MNs) from VCP-mutant and sporadic ALS, without a corresponding change in Tau protein. Using splice-switching antisense oligonucleotides and isoform-specific siRNAs, we find that enhanced 4R expression reduces MN viability, whereas its selective knockdown improves survival, with kinetics more consistent with an RNA-intrinsic effect than altered protein synthesis. Exon 10-containing MAPT RNA shows increased predicted secondary structure, self-association and altered Tau biocondensation in vitro. In post-mortem ALS cervical spinal cord, increased relative exon 10 usage is associated with a higher-risk clinical phenotype and shorter disease duration These findings identify an isoform-specific contribution of MAPT to MN vulnerability in ALS and nominate 4R MAPT RNA as a therapeutic target.
ER -